MANAGEMENT OF RISKS OF ADVERSE DRUG REACTIONS ACCORDING TO ADR REPORT FORM DATA FROM LVIV REGION HEALTHCARE FACILITIES IN 2022.

The study aimed to analyse the adverse drug reactions report form data received by the State Expert Center of the Ministry of Health of Ukraine from healthcare professionals in the Lviv region in 2022. Regarding specific types of medicines, the ones with proven cause-and-effect relationships that caused the highest frequency of adverse drug reactions incidents were chemotherapeutic agents (35.5%), medicines affecting the cardiovascular system (20.3%), and non-steroidal anti-inflammatory drugs (8%). Within the penicillin class, amoxicillin potentiated by clavulanate (67%) and amoxicillin (29%) were the dominant drugs showing the highest incidence rate of adverse reactions. Among cephalosporins, ceftriaxone (46%) and cefixime (15%) were found to take the lead in terms of adverse reaction frequency. The highest proportion among all adverse drug reactions caused by penicillins and cephalosporins was attributed to allergic reactions. To confirm or rule out immediate or delayed type allergies in patients, as well as in patients with a history of immediate-type allergic reactions to ß-lactams and planned administration of another ß-lactam, it is necessary to conduct skin testing (skin prick test, or, in the case of parenteral administration, intradermal test) with the planned ß-lactam antibiotic. The second highest proportion of induced adverse drug reactions was attributed to drugs affecting the cardiovascular system (20.3%). The leading medications in the angiotensin-converting enzyme inhibitors category were enalapril (47%) and the combination of lisinopril with hydrochlorothiazide (24%). In the angiotensin II receptor blockers category of medications, valsartan (30%) and telmisartan-hydrochlorothiazide combination (20%) ranked highest. In the category of CCB drugs, amlodipine (66%) and nifedipine (20%) held the leading positions. among angiotensin-converting enzyme inhibitors, enalapril caused the most prevalent and predicted adverse reaction, that of cough, affecting 10.5% of patients, whereas, with the combination therapy of lisinopril and hydrochlorothiazide, the cough was observed in only 5.2% of patients. Angiotensin II receptor blockers have a better safety profile, particularly concerning cough. Analysis of adverse drug reactions reports for angiotensin II receptor blockers showed no cases of cough with valsartan and telmisartan-hydrochlorothiazide combination. Among calcium channel blocker medications, amlodipine emerged to rank highest, causing one of the predicted adverse drug reactions, that of lower extremity oedema in 64% of patients. The second position was taken by the combination of amlodipine with valsartan, which showed a statistically significant reduction of 14.3% (p≤0.05) in the incidence of oedema. Using amlodipine at a dose of 5 mg in combination with sartan medicines as angiotensin receptor blockers is an effective therapeutic alternative not only for enhancing blood pressure control in hypertensive patients but also for improving the safety profile of amlodipine. Among all the non-steroidal anti-inflammatory drugs prescribed to patients in the Lviv region in 2022, the highest number of adverse reactions was associated with the administration of diclofenac, ibuprofen, paracetamol, and nimesulide, causing adverse drug reactions in 22%, 19%, 17%, and 10% of cases, respectively. The most common systemic manifestations of adverse reactions with these non-steroidal anti-inflammatory drugs were allergic reactions (63.4%) and gastrointestinal disorders (26.8%). From an evidence-based medicine perspective, the most justified approach for primary and secondary prevention of gastrointestinal complications is the use of proton pump inhibitors.

Molecular docking simulation, drug-likeness assessment, and pharmacokinetic study of some cephalosporin analogues against a penicillin-binding protein of Salmonella typhimurium.

In pursuit of novel antibiotics that could curb the growing trend of multidrug resistance by Salmonella typhimurium, a data set of some cephalosporin analogues were subjected to Molecular Docking based virtual screening against a penicillin-binding protein (PBP 1b) of the bacterium to ascertain the binding affinity values of the bioactive ligands against the active sites of the PBP 1b protein target using the AutoDock Vina Software. Three compounds with binding affinity values ranging from -7.8 kcal/mol to -8.2 kcal/mol were selected as the most promising leads. The selected compounds also displayed better potencies against the bacterium when compared with Cefuroxime (binding affinity = -6.4 kcal/mol), a standard ß-lactam antibiotic used herein for quality control and assurance. Furthermore, evaluation of the drug-likeness and ADMET properties of the three most promising leads revealed that they possess good oral bioavailability and excellent pharmacokinetic profiles. It is hoped that the findings of this study will provide an excellent template for developing more potent ß-lactam antibiotics against Salmonella typhimurium.

Role of Enzymatic Activity in the Biological Cost Associated with the Production of AmpC ß-Lactamases in Pseudomonas aeruginosa.

In the current scenario of growing antibiotic resistance, understanding the interplay between resistance mechanisms and biological costs is crucial for designing therapeutic strategies. In this regard, intrinsic AmpC ß-lactamase hyperproduction is probably the most important resistance mechanism of Pseudomonas aeruginosa, proven to entail important biological burdens that attenuate virulence mostly under peptidoglycan recycling alterations. P. aeruginosa can acquire resistance to new ß-lactam-ß-lactamase inhibitor combinations (ceftazidime-avibactam and ceftolozane-tazobactam) through mutations affecting ampC and its regulatory genes, but the impact of these mutations on the associated biological cost and the role that ß-lactamase activity plays per se in contributing to the above-mentioned virulence attenuation are unknown. The same questions remain unsolved for plasmid-encoded AmpC-type ß-lactamases such as FOX enzymes, some of which also provide resistance to new ß-lactam-ß-lactamase inhibitor combinations. Here, we assessed from different perspectives the effects of changes in the active center and, thus, in the hydrolytic spectrum resistance to inhibitors of AmpC-type ß-lactamases on the fitness and virulence of P. aeruginosa, using site-directed mutagenesis; the previously described AmpC variants T96I, G183D, and ΔG229-E247; and, finally, blaFOX-4 versus blaFOX-8. Our results indicate the essential role of AmpC activity per se in causing the reported full virulence attenuation (in terms of growth, motility, cytotoxicity, and Galleria mellonella larvae killing), although the biological cost of the above-mentioned AmpC-type variants was similar to that of the wild-type enzymes. This suggests that there is not an important biological burden that may limit the selection/spread of these variants, which could progressively compromise the future effectiveness of the above-mentioned drug combinations. IMPORTANCE The growing antibiotic resistance of the top nosocomial pathogen Pseudomonas aeruginosa pushes research to explore new therapeutic strategies, for which the resistance-versus-virulence balance is a promising source of targets. While resistance often entails significant biological costs, little is known about the bases of the virulence attenuations associated with a resistance mechanism as extraordinarily relevant as ß-lactamase production. We demonstrate that besides potential energy and cell wall alterations, the enzymatic activity of the P. aeruginosa cephalosporinase AmpC is essential for causing the full attenuation associated with its hyperproduction by affecting different features related to pathogenesis, a fact exploitable from the antivirulence perspective. Less encouraging, we also show that the production of different chromosomal/plasmid-encoded AmpC derivatives conferring resistance to some of the newest antibiotic combinations causes no significantly increased biological burdens, which suggests a free way for the selection/spread of these types of variants, potentially compromising the future effectiveness of these antipseudomonal therapies.

Occurrence of extended-spectrum ß-lactamase and AmpC-producing Escherichia coli in retail meat products from the Maritime Provinces, Canada.

This study was conducted to determine the occurrence of antimicrobial resistance to the extended-spectrum cephalosporins (ESC) in Escherichia coli isolates. The isolates were collected from retail meat products collected in the Maritime Provinces of Canada. Our analyses involved the use of both selective and traditional culture methods; we also conducted genotype analyses using multiplex polymerase chain reactions. ESC-resistant (ESC-R) E. coli were detected in 33 of 559 samples (5.9%) using the traditional culture method, compared with 151 of 557 samples (27.1%) using the selective culture method. We recovered more isolates of ESC-R E. coli from poultry compared with beef and pork (P < 0.001). Multidrug resistance, extended-spectrum ß-lactamase (ESBL), and AmpC phenotypes were more common in chicken-derived isolates than other retail meat products (P < 0.001). From the 98 isolates examined, 76 isolates (77.6%) were positive for either ESBL and AmpC ß-lactamases or both. Among the 76 isolates, blaCMY-2 (78.9%), blaCTXM (46.1%), blaTEM (21.1%), and blaSHV (1.3%) genes were detected. Among the blaCTXM-producing isolates, blaCTXM-1, blaCTXM-2, and blaCTXM-9 phylogenetic groups were detected. ß-lactamase genes were more commonly detected in chicken-derived isolates compared with other meat types (P < 0.01). This study demonstrates the occurrence of ESBL- and AmpC-resistance genes in retail meat products in the Maritime Provinces of Canada. We found that selective culture significantly improved the recovery of ESC-R E. coli isolates from retail meat samples.

Assessment of invitrosynergy of daptomycin or vancomycin plus ceftaroline for daptomycin non-susceptible Staphylococcus aureus.

The combination of vancomycin or daptomycin plus ceftaroline has showed synergistic results in vitro. This study aimed to investigate in vitro synergy of vancomycin or daptomycin plus ceftaroline for seven patients with daptomycin non-susceptible Staphylococcus aureus (SA) bacteremia Thirteen isolates from seven patients were evaluated: two methicillin-susceptible and five methicillin-resistant SA infections. All patients were treated with daptomycin and became non-susceptible (minimum inhibitory concentration (MIC) >1 µg/mL) with therapy or had resistant strains initially. Time kill experiments were completed with 0.25 × MIC, 0.5 × MIC, and 0.75 × MIC concentrations. No synergy was seen at 0.25 × MIC. Synergy was observed for 4 isolates with vancomycin plus ceftaroline and with daptomycin plus ceftaroline for 2 isolates at 0.5 × MIC. These results are in accordance with literature that supports synergistic combinations of daptomycin or vancomycin with ceftaroline for SA bacteremia. Daptomycin non-susceptible SA bacteremia presents a treatment challenge.

Multiplex High-Resolution Melting Assay for Simultaneous Identification of Molecular Markers Associated with Extended-Spectrum Cephalosporins and Azithromycin Resistance in Neisseria gonorrhoeae.

Antimicrobial resistance in Neisseria gonorrhoeae persists as a major public health concern globally. We developed and evaluated a multiplex assay that relied on high-resolution melting (HRM) technology as a rapid, simple, and cost-effective method for simultaneously detecting and identifying different molecular markers associated with extended-spectrum cephalosporins (ESCs) and azithromycin (AZM) resistance in N. gonorrhoeae. Forty-eight well-characterized N. gonorrhoeae clinical isolates were selected for initial assay establishment. The multiplex HRM assays were able to accurately identify different nucleotide variations of the antimicrobial resistance determinants related to ESCs and AZM resistance. Specificity and cross-reactivity were assessed by testing 15 nongonococcal strains. Then, the assay was validated on 218 archived DNA specimens that had been sequenced using whole-genome sequencing technology. Compared with whole-genome sequencing, these assays had a sensitivity of 98.6%, with a specificity of 99.2%. For further validation of the assay's performance, a total of 338 samples (156 clinical isolates and 182 clinical specimens) were screened using the multiplex HRM assay. The results showed good concordance with the results of PCR sequencing. Given its rapidity (within 90 minutes), ease of performing, and low cost (<$1.00 per sample), this method may be applied to large-scale epidemiologic programs for increasing surveillance of ESCs and AZM resistance in N. gonorrhoeae.

A farm-to-fork quantitative risk assessment model for Salmonella Heidelberg resistant to third-generation cephalosporins in broiler chickens in Canada.

Salmonella Heidelberg resistant to ceftiofur (a third-generation cephalosporin antimicrobial agent) in broiler chicken products pose a risk to public health in Canada. The objective of this study was to assess the extent of that risk and to evaluate the effect of intervention measures along the agri-food chain. A stochastic farm-to-fork quantitative microbial risk assessment model was developed following the Codex Alimentarius Guidelines for Risk Analysis of Foodborne Antimicrobial Resistance. Different scenarios were analyzed to assess the individual relative effects of 18 possible interventions in comparison to a baseline scenario. The baseline scenario represented the first year of on-farm antimicrobial use surveillance in the Canadian broiler industry and the year before an industry-imposed ban on the preventive use of antimicrobials of very high importance to human health (2013), where 31.3% of broiler flocks consisted of birds to which ceftiofur was administered. The baseline scenario predicted an average probability of illness of 1.1 per 100,000 servings (SE: 0.064 per 100,000), corresponding to an average of 22,000 human infections (SE: 1900) with ceftiofur-resistant S. Heidelberg per year, which is likely an overestimation. This risk was reduced by 90% or 20% when two separate scenarios designed to capture the effect of withdrawing preventive ceftiofur use from poultry production were simulated using different approaches; data used for the former scenario were confounded by other potential concomitant control measures (e.g. Salmonella vaccination programme), so the true effect likely lies somewhere between the two estimates. A theoretical 'worst case' scenario where all flocks had birds exposed to ceftiofur increased the risk by 107%. A 50% reduction in the probability of human prior exposure to antimicrobials, which has a selective and competitive effect for Salmonella spp. following ingestion of contaminated products, reduced the risk by 65%. Other promising measures that could be considered for further risk management included improved cleaning and disinfection between broiler flocks on farm (risk reduction by 26%), exclusive use of air chilling (risk reduction by 34%), and the improvement of meat storage and preparation conditions, e.g., no temperature abuse at retail (risk reduction by 88%). These findings showed the importance of a structured approach to assessing and potentially implementing effective interventions to reduce the risk associated with ceftiofur-resistant S. Heidelberg at different steps along the agri-food chain. Major data gaps included information on concentrations of resistant bacteria, cross contamination at processing and how ceftiofur-resistant S. Heidelberg behave in comparison with susceptible ones, e.g., in terms of growth and survival ability, as well as pathogenicity and virulence.

Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration.

BACKGROUND: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC. METHODS: Steady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. RESULTS: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively. CONCLUSIONS: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

Econometric ARIMA methodology to elucidate the evolution of trends in nosocomial antimicrobial resistance rates in the European Union.

BACKGROUND: Infections with bacteria harbouring resistance to cephalosporins or fluoroquinolones (FQ) constitute a serious hazard to human health. OBJECTIVES: To establish a methodology based on econometric analysis and the largest European Union (EU) resistance database (EARS-Net), to model nosocomial antimicrobial resistance (AMR) in the EU and to detect tendency changes, steps or peaks. The contribution of legislation based on third-generation cephalosporin (3GC) and FQ class referrals to resistance rate patterns is evaluated. METHODS: Resistance to 3GC and FQ was examined in nosocomial Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in at least 25 out of 30 EU countries (> 94% population coverage), weighted by their mean annual population, between 2006 and 2016. Autoregressive integrated moving average (ARIMA) model analysis, inspired by Box-Jenkins methodology, was prepared to adjust series to a mathematical model to detect hypothetical changes in the general behaviour. To the best of the authors' knowledge, this is the first study to use ARIMA with interventions to model overall nosocomial AMR data compiled in EARS-Net. RESULTS AND CONCLUSIONS: Econometric ARIMA models statistically prove the occurence of slowdowns and reversions in the increasing trend of AMR prevalence in nosocomial E. coli and K. pneumoniae to 3GC and FQ, as well as resistance of P. aeruginosa to 3GC. The resistance of P. aeruginosa to FQ exhibited a descending slope. The presented decreasing trends constitute noteworthy milestones in tackling AMR in Europe.

Ceftiofur-resistant Salmonella enterica serovar Heidelberg of poultry origin - a risk profile using the Codex framework.

Codex published the 'Guidelines for Risk Analysis of Foodborne Antimicrobial Resistance' to standardise the approach for evaluating risk posed by foodborne antimicrobial-resistant bacteria. One of the first steps in the guidelines is to compile a risk profile, which provides the current state of knowledge regarding a food safety issue, describes risk management options and recommends next steps. In Canada, ceftiofur/ceftriaxone-resistant Salmonella enterica subsp. enterica serovar Heidelberg from poultry was identified as an antimicrobial resistance (AMR) food safety issue. The first objective of this article was to contextualise this food safety issue, using the risk profile format of the Codex Guidelines. A second objective was to evaluate the applicability of the Codex Guidelines. This risk profile indicated that ceftiofur/ceftriaxone-resistant S. Heidelberg (CSH) was commonly isolated from poultry and was associated with severe disease in humans. Ceftiofur use in poultry hatcheries temporally mirrored the prevalence of CSH from poultry meat at retail and from people with salmonellosis. The evidence was sufficient to indicate the need for risk management options, such as restricting the use of ceftiofur in poultry. The Codex Guidelines provided a useful approach to summarise data for decision-makers to evaluate an AMR food safety issue.

Assessment of Inhibition of Bovine Hepatic Cytochrome P450 by 43 Commercial Bovine Medicines Using a Combination of In Vitro Assays and Pharmacokinetic Data from the Literature.

BACKGROUND: There has been a lack of information about the inhibition of bovine medicines on bovine hepatic CYP450 at their commercial doses and dosing routes. OBJECTIVE: The aim of this work was to assess the inhibition of 43 bovine medicines on bovine hepatic CYP450 using a combination of in vitro assay and Cmax values from pharmacokinetic studies with their commercial doses and dosing routes in the literature. METHODS: Those drugs were first evaluated through a single point inhibitory assay at 3 µM in bovine liver microsomes for six specific CYP450 metabolisms, phenacetin o-deethylation, coumarin 7- hydroxylation, tolbutamide 4-hydroxylation, bufuralol 1-hydroxylation, chlorzoxazone 6-hydroxylation and midazolam 1'-hydroxylation. When the inhibition was greater than 20% in the assay, IC50 values were then determined. The potential in vivo bovine hepatic CYP450 inhibition by those drugs was assessed using a combination of the IC50 values and in vivo Cmax values from pharmacokinetic studies at their commercial doses and administration routes in the literature. RESULTS: Fifteen bovine medicines or metabolites showed in vitro inhibition on one or more bovine hepatic CYP450 metabolisms with different IC50 values. Desfuroylceftiour (active metabolite of ceftiofur), nitroxinil and flunixin have the potential to inhibit one of the bovine hepatic CYP450 isoforms in vivo at their commercial doses and administration routes. The rest of the bovine medicines had low risks of in vivo bovine hepatic CYP450 inhibition. CONCLUSION: This combination of in vitro assay and in vivo Cmax data provides a good approach to assess the inhibition of bovine medicines on bovine hepatic CYP450.

Decreasing and stabilising trends of antimicrobial consumption and resistance in Escherichia coli and Klebsiella pneumoniae in segmented regression analysis, European Union/European Economic Area, 2001 to 2018.

Investments to reduce the spread of antimicrobial resistance (AMR) in the European Union have been made, including efforts to strengthen prudent antimicrobial use. Using segmented regression, we report decreasing and stabilising trends in data reported to the European Surveillance of Antimicrobial Consumption Network and stabilising trends in data reported to the European Antimicrobial Resistance Surveillance Network. Our results could be an early indication of the effect of prioritising AMR on the public health agenda.

Direct medical costs of urinary tract infections by Gram-negative bacilli resistant to beta-lactams in a tertiary care hospital in Medellín, Colombia / Costos médicos directos de las infecciones del tracto urinario por bacilos Gram negativos resistentes a betalactámicos en un hospital de alta complejidad de Medellín, Colombia

Introduction: Urinary tract infections are very frequent in the hospital environment and given the emergence of antimicrobial resistance, they have made care processes more complex and have placed additional pressure on available healthcare resources. Objective: To describe and compare excess direct medical costs of urinary tract infections due to Klebsiella pneumoniae, Enterobacter cloacae and Pseudomonas aeruginosa resistant to beta-lactams. Materials and methods: A cohort study was conducted in a third level hospital in Medellín, Colombia, from October, 2014, to September, 2015. It included patients with urinary tract infections caused by beta-lactam-susceptible bacteria, third and fourth generation cephalosporin-resistant, as well as carbapenem-resistant. Costs were analyzed from the perspective of the health system. Clinical-epidemiological information was obtained from medical records and the costs were calculated using standard tariff manuals. Excess costs were estimated with multivariate analyses. Results: We included 141 patients: 55 (39%) were sensitive to beta-lactams, 54 (38.3%) were resistant to cephalosporins and 32 (22.7%) to carbapenems. The excess total adjusted costs of patients with urinary tract infections due to cephalosporin- and carbapenem-resistant bacteria were US$ 193 (95% confidence interval (CI): US$ -347-734) and US$ 633 (95% CI: US$ -50-1316), respectively, compared to the group of patients with beta-lactam sensitive urinary tract infections. The differences were mainly found in the use of broad-spectrum antibiotics such as meropenem, colistin, and fosfomycin. Conclusion: Our results show a substantial increase in the direct medical costs of patients with urinary tract infections caused by beta-lactam-resistant Gram-negative bacilli (cephalosporins and carbapenems). This situation is of particular concern in endemic countries such as Colombia, where the high frequencies of urinary tract infections and the resistance to beta-lactam antibiotics can generate a greater economic impact on the health sector.

Introducción. Las infecciones del tracto urinario son muy frecuentes en el ámbito hospitalario. Debido a la aparición de la resistencia antimicrobiana, la complejidad de los procesos de atención ha aumentado y, con ello, la demanda de recursos. Objetivo. Describir y comparar el exceso de los costos médicos directos de las infecciones del tracto urinario por Klebsiella pneumoniae, Enterobacter cloacae y Pseudomonas aeruginosa resistentes a betalactámicos. Materiales y métodos. Se llevó a cabo un estudio de cohorte en una institución de tercer nivel de Medellín, Colombia, entre octubre del 2014 y septiembre del 2015. Se incluyeron los pacientes con infección urinaria, unos por bacterias sensibles a los antibióticos betalactámicos, y otros por bacterias resistentes a las cefalosporinas de tercera y cuarta generación y a los antibióticos carbapenémicos. Los costos se analizaron desde la perspectiva del sistema de salud. La información clínico-epidemiológica se obtuvo de las historias clínicas y los costos se calcularon utilizando los manuales tarifarios estándar. El exceso de costos se estimó mediante análisis multivariados. Resultados. Se incluyeron 141 pacientes con infección urinaria: 55 (39 %) por bacterias sensibles a los betalactámicos, 54 (38,3 %) por bacterias resistentes a las cefalosporinas y 32 (22,7 %) por bacterias resistentes a los carbapenémicos. El exceso de costos totales ajustado de los 86 pacientes con infecciones del tracto urinario por bacterias resistentes a las cefalosporinas y a los carbapenémicos, fue de USD$ 193 (IC95% -347 a 734) y USD$ 633 (IC95% -50 a 1.316), respectivamente comparados con el grupo de 55 pacientes por bacterias sensibles a los betalactámicos. Las diferencias se presentaron principalmente en el uso de antibióticos de amplio espectro, como el meropenem, la colistina y la fosfomicina. Conclusión. Los resultados evidenciaron un incremento sustancial de los costos médicos directos de los pacientes con infecciones del tracto urinario por bacterias resistentes a las cefalosporinas o a los carbapenémicos. Esta situación genera especial preocupación en los países endémicos como Colombia, donde la alta frecuencia de infecciones del tracto urinario y de resistencia a los betalactámicos puede causar un mayor impacto económico en el sector de la salud.

Assessment of the In Vitro Activities of Ceftolozane/Tazobactam and Ceftazidime/Avibactam in a Collection of Beta-Lactam-Resistant Enterobacteriaceae and Pseudomonas aeruginosa Clinical Isolates at Montpellier University Hospital, France.

Objective: To assess in vitro ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA) activity in beta-lactam-resistant Enterobacteriaceae and Pseudomonas aeruginosa clinical isolates from major carbapenem-using Departments at Montpellier University Hospital, France. Materials and Methods: We tested third-generation cephalosporin-resistant Enterobacteriaceae (by production of extended spectrum ß-lactamase or other mechanisms, mainly AmpC beta-lactamases) and ceftazidime- and/or carbapenem-resistant P. aeruginosa strains isolated from clinical samples of patients hospitalized from January 2017 to May 2017 and August 2016 to July 2017, respectively. We also included all OXA-48 beta-lactamase-producing Enterobacteriaceae strains isolated in the whole hospital from October 2015 to May 2017. We used the 2017 European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines for minimal inhibitory concentration interpretation. Results: Among the 62 cephalosporin-resistant Enterobacteriaceae strains, 60 (97%) were susceptible to CZA and 34 (65%) to C/T. The two CZA-resistant Klebsiella pneumoniae isolates produced (i) NDM-carbapenemase and extended-spectrum beta-lactamase (ESBL) and (ii) ESBL CTXM-15 and OXA-1 associated with impermeability. Moreover, 31 of the 42 P. aeruginosa strains (74%) were susceptible to CZA and 37 (88%) to C/T. Finally, 26/27 (96%) of OXA-48 beta-lactamase-producing Enterobacteriaceae were susceptible to CZA and 8/27 (30%) to C/T. Conclusions: At our hospital, CZA and C/T offer a carbapenem-sparing alternative for resistant gram-negative pathogens and could be a salvage therapy for carbapenem-resistant pathogens.

Nationwide survey of indications for oral antimicrobial prescription for pediatric patients from 2013 to 2016 in Japan.

BACKGROUND: Antimicrobial resistance is a major public health concern. In 2016, the Japanese government launched a national action plan aimed at achieving a 33% and 50% reduction in the number of total and oral antimicrobial prescriptions (cephalosporins, macrolides, and quinolones) from the 2013 figures by 2020, respectively. The purpose of this study was to investigate the indications for recent antimicrobial prescriptions and to identify the primary targets for intervention to achieve the aims of the government's action plan. METHODS: Using the national health claims database, we retrospectively analyzed oral antibiotic prescriptions for Japanese children aged ≦ 15 years from 2013 to 2016. The trends were analyzed based on days of therapy (DOT) per infectious disease-related visit for each antibiotic. For patients whose chief diagnosis was an infectious disease, the number of antimicrobial prescriptions per diagnosis, their proportion, and the details of the type of antimicrobial were investigated. RESULTS: In total, 297,197,328 infectious disease-related visits were identified during 2013-2016. Total antimicrobial prescriptions showed a 3.7% reduction from 1.519 DOT/visitor in 2013 to 1.463 DOT/visitor in 2016 (Ptrend < 0.001). Antimicrobials were prescribed for 31.7% and 36.9% of children with upper and lower respiratory tract infection, accounting for 54.6% and 26.2% of all antimicrobial prescriptions, respectively. Third generation cephalosporins and macrolides comprised the majority of these prescriptions. CONCLUSIONS: Antimicrobials were commonly prescribed for children with respiratory infections. Therefore, promoting appropriate antimicrobial use in this population is required to achieve the 2020 goals set by the action plan.

Costos médicos directos de las infecciones del tracto urinario por bacilos Gram negativos resistentes a betalactámicos en un hospital de alta complejidad de Medellín, Colombia / Direct medical costs of urinary tract infections by Gram-negative bacilli resistant to beta-lactams in a tertiary care hospital in Medellín, Colombia

Resumen Introducción. Las infecciones del tracto urinario son muy frecuentes en el ámbito hospitalario. Debido a la aparición de la resistencia antimicrobiana, la complejidad de los procesos de atención ha aumentado y, con ello, la demanda de recursos. Objetivo. Describir y comparar el exceso de los costos médicos directos de las infecciones del tracto urinario por Klebsiella pneumoniae, Enterobacter cloacae y Pseudomonas aeruginosa resistentes a betalactámicos. Materiales y métodos. Se llevó a cabo un estudio de cohorte en una institución de tercer nivel de Medellín, Colombia, entre octubre del 2014 y septiembre del 2015. Se incluyeron los pacientes con infección urinaria, unos por bacterias sensibles a los antibióticos betalactámicos, y otros por bacterias resistentes a las cefalosporinas de tercera y cuarta generación y a los antibióticos carbapenémicos. Los costos se analizaron desde la perspectiva del sistema de salud. La información clínico-epidemiológica se obtuvo de las historias clínicas y los costos se calcularon utilizando los manuales tarifarios estándar. El exceso de costos se estimó mediante análisis multivariados. Resultados. Se incluyeron 141 pacientes con infección urinaria: 55 (39 %) por bacterias sensibles a los betalactámicos, 54 (38,3 %) por bacterias resistentes a las cefalosporinas y 32 (22,7 %) por bacterias resistentes a los carbapenémicos. El exceso de costos totales ajustado de los 86 pacientes con infecciones del tracto urinario por bacterias resistentes a las cefalosporinas y a los carbapenémicos, fue de USD$ 193 (IC95% -347 a 734) y USD$ 633 (IC95% -50 a 1.316), respectivamente comparados con el grupo de 55 pacientes por bacterias sensibles a los betalactámicos. Las diferencias se presentaron principalmente en el uso de antibióticos de amplio espectro, como el meropenem, la colistina y la fosfomicina. Conclusión. Los resultados evidenciaron un incremento sustancial de los costos médicos directos de los pacientes con infecciones del tracto urinario por bacterias resistentes a las cefalosporinas o a los carbapenémicos. Esta situación genera especial preocupación en los países endémicos como Colombia, donde la alta frecuencia de infecciones del tracto urinario y de resistencia a los betalactámicos puede causar un mayor impacto económico en el sector de la salud.

Abstract Introduction: Urinary tract infections are very frequent in the hospital environment and given the emergence of antimicrobial resistance, they have made care processes more complex and have placed additional pressure on available healthcare resources. Objective: To describe and compare excess direct medical costs of urinary tract infections due to Klebsiella pneumoniae, Enterobacter cloacae and Pseudomonas aeruginosa resistant to beta-lactams. Materials and methods: A cohort study was conducted in a third level hospital in Medellín, Colombia, from October, 2014, to September, 2015. It included patients with urinary tract infections caused by beta-lactam-susceptible bacteria, third and fourth generation cephalosporin-resistant, as well as carbapenem-resistant. Costs were analyzed from the perspective of the health system. Clinical-epidemiological information was obtained from medical records and the costs were calculated using standard tariff manuals. Excess costs were estimated with multivariate analyses. Results: We included 141 patients: 55 (39%) were sensitive to beta-lactams, 54 (38.3%) were resistant to cephalosporins and 32 (22.7%) to carbapenems. The excess total adjusted costs of patients with urinary tract infections due to cephalosporin- and carbapenem-resistant bacteria were US$ 193 (95% confidence interval (CI): US$ -347-734) and US$ 633 (95% CI: US$ -50-1316), respectively, compared to the group of patients with beta-lactam sensitive urinary tract infections. The differences were mainly found in the use of broad-spectrum antibiotics such as meropenem, colistin, and fosfomycin. Conclusion: Our results show a substantial increase in the direct medical costs of patients with urinary tract infections caused by beta-lactam-resistant Gram-negative bacilli (cephalosporins and carbapenems). This situation is of particular concern in endemic countries such as Colombia, where the high frequencies of urinary tract infections and the resistance to beta-lactam antibiotics can generate a greater economic impact on the health sector.

A novel disk-based detection method with superior sensitivity for ß-lactamase production in third-generation cephalosporin-resistant Enterobacteriaceae.

OBJECTIVE: Current phenotypic methods for extended-spectrum ß-lactamase (ESBL), AmpC ß-lactamase (AmpC), and carbapenemases fail to detect isolates that co-produce other classes of ß-lactamases. In this study, we have developed a novel assay (Applied Multiplex Disk Method: AMU-DM) for the phenotypic detection and identification of ß-lactamases produced by Enterobacteriaceae. METHODS: We evaluated the performance of the method by comparison with PCR results for 78 Enterobacteriaceae clinical isolates that were positive by the ESBL screening test and negative by the ESBL confirmation test. Additionally, one NCTC strain and four ATCC strains were also included in the test population for the study as reference. RESULTS: For 79/83 (95%) isolates tested, the AMU-DM results matched those obtained by PCR. The concordance rates were 31/31 (100%), 11/11 (100%), 3/3 (100%), 0/1 (0%), 15/15 (100%), 16/19 (84%), and 3/3 (100%) for AmpC, ESBL and AmpC co-production, Klebsiella pneumoniae carbapenemase (KPC), KPC and ESBL co-production, metallo ß-lactamase (MBL), MBL and ESBL co-production, and MBL and AmpC co-production, respectively. CONCLUSION: The AMU-DM is convenient to perform, economical, and highly sensitive in identifying ESBLs, AmpCs, and carbapenemases. Our method may be useful in clinical settings for the implementation of relevant infection control measures and for surveillance purposes.

Assessment of the In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Murine Lung Infection Model.

We evaluated the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) against cefepime-resistant Acinetobacter baumannii strains (n = 13) in the neutropenic murine lung infection model. Twelve isolates were meropenem resistant. In control animals and those that received cefepime or zidebactam alone, the mean bacterial growth at 24 h was >2 log10 CFU/lung compared with 0-h controls (6.32 ± 0.33 log10 CFU/lung). WCK 5222 produced a decline in the bacterial burden for all isolates (mean reduction, -3.34 ± 0.85 log10 CFU/lung) and demonstrated remarkable potency.

Pharmacokinetic/pharmacodynamic assessment of cefquinome against Actinobacillus Pleuropneumoniae in a piglet tissue cage infection model.

To evaluate the relationship between the pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect of cefquinome against Actinobacillus pleuropneumoniae, a tissue cage infection model was established in piglets. In this model, an initial count of A. pleuropneumoniae of approximately 106 CFU/mL was exposed to different concentrations of cefquinome after multiple administration at dosages of 0.2, 0.4, 0.8, 1, 2, 4 mg/kg body weight once a day for 3 days. Concentration of cefquinome and bacterial numbers of A. pleuropneumoniae in the tissue-cage fluid (TCF) were monitered. An inhibitory form of sigmoid maximum effect (Emax) model was used to estimate the relationship between the antibacterial effect and PK/PD indices of cefquinome against A. pleuropneumoniae. The minimum inhibitory concentration of cefquinome against A. pleuropneumoniae was 0.016 µg/mL in TCF. The total maximum antibacterial effect was a 3.96 log10 (CFU/mL) reduction. In addition, the cumulative percentage of time over a 24 h period that the drug concentration exceeds the MIC (%T > MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best correlated with the antibacterial efficacy (R2 = 0.967). The estimated %T > MIC values were 11.59, 27.49, and 59.81% for a 1/3-log10 (CFU/mL) reduction, a 2/3-log10 (CFU/mL) reduction, and a 1-log10 (CFU/mL) reduction, respectively, during the 24h administration period of cefquinome. In conclusion, cefquinome exhibits excellent antibacterial activity and time-dependent characteristics against A. pleuropneumoniae in vivo. Furthermore, these data provide meaningful guidance to optimize regimens of cefquinome to treat respiratory tract infections caused by A. pleuropneumoniae.